N-substituted azaheterocyclic carboxylic acids

ABSTRACT

Novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which an ether group forms part of the N-substituent, the compounds thus having the general formula I ##STR1## wherein R 1  and R 2  are the same or different and each represents phenyl, 2-thienyl or 3-thienyl, 2-pyrrolyl- or 3-pyrrolyl, substituted with one or more substituents selected among the following atoms or groups: hydrogen, halogen, C 1-6  -alkyl, C 1-6  -alkoxy or cyano; R 3  and R 4  each represents hydrogen or together represent a bond; m is 1 or 2 and n is 1 when m is 1 and n is 0 when m is 2; R 5  and R 6  each represents hydrogen or may--when m is 2--together represent a bond, and R 7  is OH or C 1-8  -alkoxy, p is 0 or 1 or 2, q is 0 or 1 or 2, R 8  is H and C 1-4  -alkyl, are potent inhibitors of GABA uptake from the synaptic cleft.

This is a continuation application of co-pending application Ser. No.07/450,805, filed Dec. 14, 1989, now U.S. Pat. No. 5,071,859.

The present invention relates to novel N-substituted azaheterocycliccarboxylic acids and esters thereof, in which an alkyl ether group formspart of the N-substituent and salts thereof, to methods for theirpreparation, to compositions containing them, and to their use for theclinical treatment of abnormal function of γ-aminobutyric acidneurotransmission system.

In recent years much pharmacological research concerning γ-aminobutyricacid (hereinafter designated GABA), an inhibitory neurotransmitter inthe mammalian central nervous system, has been carried out.

The inhibition of GABA uptake results in enhanced availability of thisinhibitory neurotransmitter in the synaptic cleft and thus to increasedGABA'ergic activity. Increased GABA'ergic activity can be useful in thetreatment, e.g. of anxiety, pain and epilepsy, as well as muscular andmovement disorders (see for example Krogsgaard-Larsen, P. et al.,Progress in Medicinal Chemistry 22 (1985) 68-11, Advances in DrugResearch, 17 (1988), 381-456.

A well-known and potent inhibitor of GABA uptake from the synaptic cleftinto presynaptic nerve terminals and glial cells is, for example,piperidine-3-carboxylic acid (nipecotic acid) However, being arelatively polar compound and therefore unable to cross the blood-brainbarrier, piperidine-3-carboxylic acid itself has found no practicalutility as a drug.

In U.S. patent specifications No. 4,383,999 and No. 4,514,414(SmithKline Beckman Corporation) and European patent applications No.86903274 and No. 87300064 (Novo Industri A/S) some derivatives ofN-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids areclaimed as inhibitors of GABA uptake. In Danish patent application No.2704/88 (Novo Industri A/S) N-substituted azaheterocyclic carboxylicacids in which an oxime ether group forms part of the N-substituent areclaimed as inhibitors of GABA uptake. European patent application No.86115478.9 (Warner-Lambert Company) claims that1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

According to Yunger, L.M. et al., J. Pharm. Exp. Therap., 228 (1984)109, N-(4,4-diphenyl-3-butenyl)nipecotic acid (designated SK&F 89976A),N-(4,4-diphenyl-3-butenyl)guvacine (designated SK&F 100330A),N-(4,4-diphenyl-3-butenyl)homo-β-proline (designated SK&F 100561) andN-(4-phenyl-4-(2-thienyl)-3-butenyl)nipecotic acid (designated SK&F100604J) are orally active inhibitors of GABA uptake. These data aresummarized in Krogsgaard-Larsen, P. et al., Epilepsy Res., 1 (1987)77-93.

Nipecotic acid is piperidine-3-carboxylic acid, guvacine is1,2,5,6-tetrahydropyridine-3-carboxylic acid and homo-β-proline ispyrrolidine-3-acetic acid.

The present invention relates to novel N-substituted azaheterocycliccarboxylic acids and esters thereof in which an ether group forms partof the N-substituent. The compounds according to the invention have thegeneral formula I ##STR2## wherein R¹ and R² are the same or differentand each represents phenyl, 2-pyrrolyl or 3-pyrrolyl, 2-thienyl or3-thienyl, substituted with one or more substituents selected among thefollowing atoms or groups: hydrogen, halogen, C₁₋₆ -alkyl, C₁₋₆ - alkoxyor cyano; R³ and R⁴ each represents hydrogen or together represent abond; m is 1 or 2 and n is 1 when m is 1 and n is 0 when m is 2; R⁵ andR⁶ each represents hydrogen or may - when m is 2 - together represent abond, and R⁷ is OH or C p is 0 or 1 or 2, q is 0 or 1 or 2, R⁸ is H andC₁₋₄ -alkyl. When R¹ and/or R² is pyrrolyl the substituent on the N-atomcan be either hydrogen or C₁₋₄ - alkyl. The compounds according to theinvention may optionally exist as pharmaceutically acceptable acidaddition salts or--when the carboxylic acid group is not esterified--aspharmaceutically acceptable metal salts or--optionallyalkylated--ammonium salts. The compounds of formula I have a greaterlipophilicity--and thus a greater availabililty to the brain--as well asa far higher affinity to the GABA uptake sites than the parent compoundswithout the N-substituent (e.g. pyrrolidine-3-acetic acid(homo-β-proline), piperidine-3-carboxylic acid (nipecotic acid) and1,2,5,6-tetrahydropyridine-3-carboxylic acid (guvacine)). They thereforepossess interesting and useful pharmacological properties.

The compounds of formula I may exist as geometric and optical isomersand all isomers and mixtures thereof are included herein. Isomers may beseparated by means of standard methods such as chromatographictechniques or fractional crystallization of salts with optically activeacids or bases.

It has been demonstrated that the novel compounds of the general formulaI, which inhibit the uptake of GABA from the synaptic cleft possessuseful pharmacological properties on the central nervous system, in thatthey cause a selective enhancement of GABA'ergic activity. Compounds offormula I may be used to treat, for example, pain, anxiety, epilepsy andcertain muscular and movement disorders. They may also find use assedatives, hypnotics and antidepressants.

Pharmaceutically acceptable acid addition salts of compounds of formulaI include those derived from inorganic or organic acids such ashydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, maleic,phthalic, citric and fumaric acid.

The compounds according to the invention are prepared according to oneof the following methods:

METHOD A

Compounds having the general formula Ia i.e. compounds of the generalformula I as defined above in which R³ and R⁴ together form a bond maybe prepared by the following method A: ##STR3##

An acetaldehyde derivative of formula II wherein R¹ and R² are asdefined above is allowed to react with a compound of formula III whereinY is a suitable leaving group such as halogen or p-toluene sulphonate.This reaction may be carried out in a suitable solvent such astetrahydrofuran, toluene or N,N-dimethylformamide in the presence of astrong base such as sodium hydride at a temperature up to refluxtemperature for e.g. 1 to 72 h (for examples of the synthesis ofacetaldehyde derivatives of formula II, see Meyers, A.I. et al., J.Amer. Chem. Soc., 104 (1982) 877-9 Matteson, D.S. et al., J. Org. Chem.,45 (1980) 1091-5). Blicke, F.F. and Faust, J.A., J. Amer. Chem. Soc., 16(1954), 3156; Borch R.F., Tetrahedron Lett., 36, (1972), Martin, S.F.,Synthesis, (1979), 633; Ashwood M.S. et al., Synthesis, (1988), 379)).

METHOD B

Compounds having the general formula I as defined above may be preparedby the following general method B: ##STR4##

A hydroxy ether derivative of general formula IV wherein R¹, R², R³, R⁴,R⁸, p and q are as defined above, is allowed to react to form a compoundof formula V, wherein R¹, R², R³, R⁴, R⁸, p and q are as defined aboveand Z is a suitable leaving group (i.e. halogen, tosylate, mesylate).This reaction may be carried out in a suitable solvent (e.g.dichloromethane, toluene, pyridine) with the appropriate reagent (e.g.p-toluenesulphonyl chloride, phosphorus oxychloride, phosphoruspentachloride thionyl halide, phosphorus tribromide or methanesulphonylchloride) at a temperature up to reflux temperature for e.g. 1 to 72 h.The ether derivative of formula V, wherein R¹, R², R³, R⁴, R⁸, Z, p andq are as defined above is allowed to react with an amino acid derivativeof formula VI wherein R⁵, R⁶, R⁷, n and m are as defined above, to forma compound of general formula I. This reaction may be carried out in asuitable solvent such as acetone, tetrahydrofuran, toluene orN,N-dimethylformamide in the presence of a base such as an alkali metalcarbonate or a suitable tertiary amine at a temperature up to refluxtemperature for e.g. 1 to 72 h.

METHOD C

Compounds having the general formula Ia as defined above (Method A) maybe prepared by the following Method C: ##STR5##

An acetaldehyde derivative of formula II las defined in Method A) isallowed to react with a disubstituted alkane of formula VII, wherein R⁸,p and q are as defined above and Y and Z are suitable leaving groups(such as halogen, tosylate or mesylate) (Y and Z may be the same ordifferent) to form a vinyl ether derivative of formula VIII. Thisreaction may be carried out in a suitable solvent such astetrahydrofuran, toluene or N,N-dimethylformamide in the presence of astrong base, such as sodium hydride or an alkyllithium at a temperatureup to reflux temp. for e.g. 1 to 72 h.

The vinyl ether derivative of formula VIII is allowed to react with anamino acid derivative of formula VI (in much the same way as compound Vreacts with VI in Method B) to form a compound of general formula Ia,wherein R¹, R², R⁵, R⁶, R⁷, R⁸, n, m, p and q are as defined above.

METHOD D

Compounds having the general formula Ia as defined above (Method A) maybe prepared by the following method D: ##STR6##

This method is superficially similar to Method C, but with the importantdifference that the vinyl ether derivative of formula VIII is preparedby a phase-transfer reaction of the aldehyde derivative (II) with thedisubstituted alkane of formula VII. The substituents are as defined inMethod C.

Examples of such phase transfer alkylations may be found in W. E.Keller, Phase Transfer Reactions, Vol. 1 and 2, Fluka, Georg ThiemeVerlag, Stuttgart 1986 and 1989.

METHOD E

Compounds having the general formula Ib, i.e. compounds of the generalformula I as defined above, in which R³, R⁴, R⁵ and R⁶ are all hydrogenand m is 2 and n is O, can be prepared by hydrogenating compounds offormula Ia: ##STR7##

The hydrogenation is preferably carried out at room temperature in thepresence of a hydrogenation catalyst such as a noble metal catalyst,e.g. palladium on charcoal. The preferred hydrogen pressure is fromatmospheric pressure up to about 5 atm., however, the hydrogenation canalso be performed at high pressure. Ethanol and methanol are examples ofpreferred solvents.

Under certain circumstances it may be necessary to protect theintermediates used in the above methods (e.g. III or V) with suitableprotecting groups. The carboxylic acid group can for example beesterified. Introduction and removal of such groups is described e.g. in"Protective Groups in Organic Chemistry"J. F. W. McOrnie ed. (New York,1973).

If esters have been prepared in methods A-E, compounds of formula Iwherein R⁷ is OH may be prepared by hydrolysis of the ester group,preferably at room temperature in a mixture of an aqueous alkali metalhydroxide solution and an alcohol such as methanol or ethanol, forexample for about 0.5 to 6 h.

PHARMACOLOGICAL METHODS

Values for in vitro inhibition of [³ H]-GABA uptake for these compoundswere assessed essentially by the method of Fjalland (Acta Pharmacol.Toxicol. 42 (1978) 73-76).

Male Wistar rat cortical tissue was gently homogenized by hand using aglass/PTFE homogenizer in 10 volumes of 0.32 M sucrose. Incubation wasperformed in a 40 mM tris HCl buffer (pH 7.5 at 30° C.) containing 120nM NaCl, 9.2 nM KCl, 4 mM MgSO₄, 2.3 mM CaCl₂ and 10 mM glucose, for 60min. at 30° C. Ligand concentration was 0.2 nM.

Values for inhibition of GABA uptake for some representative compoundsare recorded in the table below.

                  TABLE 1                                                         ______________________________________                                        Inhibition of [.sup.3 H]-GABA uptake                                          Product from                                                                  Example No.   IC.sub.50 (nm) in vitro                                         ______________________________________                                         2            104                                                             12             8                                                              13            26                                                              33            127                                                             14            30                                                              17            15                                                              23            47                                                              30            12                                                              ______________________________________                                    

Compounds of formula I are useful because they possess significantpharmacological activity in man. In particular the compounds of formulaI are useful as a consequence of their inhibition of GABA uptake.

For the above indications the dosage will vary depending on the compoundof formula I employed, on the mode of administration and on the therapydesired. However, in general, satisfactory results are obtained with adosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mgto about 500 mg of compounds of formula I, conveniently given from 1 to5 times daily, optionally in sustained release form. Usually, dosageforms suitable for oral administration comprise from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg of thecompounds of formula I admixed with a pharmaceutical carrier or diluent.No toxic effects have been observed.

The compounds of formula I may be administered in pharmaceuticallyacceptable acid addition salt form or where possible as a metal or alower alkylammonium salt. Such salt forms exhibit approximately the sameorder or activity as the free base forms.

This invention also relates to pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt thereof and,usually such compositions also contain a pharmaceutical carrier ordiluent. The compositions containing the compounds of this invention maybe prepared by conventional techniques and appear in conventional forms,for example capsules, tablets, solutions or suspensions.

The pharmaceutical carrier employed may be a conventional solid orliquid carrier. Examples of solid carriers are lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate andstearic acid. Examples of liquid carriers are syrup, peanut oil, oliveoil and water.

Similarly, the carrier or diluent may include any time delay materialknown to the art, such as glyceryl monostearate or glyceryl distearate,alone or mixed with a wax.

If a solid carrier for oral administration is used, the preparation canbe tabletted, placed in a hard gelatin capsule in powder of pellet form,or it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely, but will usually be from about 25 mg to about1 g. If a liquid carrier is used, the preparation may be in the form ofa syrup, emulsion, soft gelatin capsule or sterile injectable liquidsuch as an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical compositions of this invention can be made followingthe conventional techniques of the pharmaceutical industry involvingmixing, granulating and compressing or variously mixing and dissolvingthe ingredients as appropriate to give the desired end product.

The route of administration may be any route, which effectivelytransports the active compound to the appropriated or desired site ofaction, such as oral or parenteral, the oral route being preferred.

A typical tablet which may be prepared by conventional tablettingtechniques contains:

    ______________________________________                                        Core:                                                                         Active compound (as free compound                                                                    100       mg                                           or salt thereof)                                                              Colloidal silicon dioxide (Areosil ®)                                                            1.5       mg                                           Cellulose, microcryst. (Avicel ®)                                                                70        mg                                           Modified cellulose gum (Ac-Di-Sol ®)                                                             7.5       mg                                           Magnesium stearate     1         mg                                           Coating:                                                                      HPMC                   approx. 9 mg                                           *Mywacett ® 9-40 T approx. 0.9                                                                             mg                                           ______________________________________                                         *Acylated monoglyceride used as plasticizer for filmcoating              

The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral, the oral route being preferred.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples which,however, are not to be construed as limiting. The examples illustratesome preferred embodiments.

Hereinafter, TLC is thin layer chromatography, THF is tetrahydrofuran,TFA is trifluoroacetic acid and m.p. is melting point. The structures ofthe compounds are confirmed by NMR and elemental analysis. Where meltingpoints are given, these are uncorrected. All temperatures are in ° C.Compounds used as starting materials are either known compounds orcompounds which can readily be prepared by methods known per se. Noveldiarylacetaldehydes were prepared by known methods (see e.g. Blicke, FFand Faust, J.A., J. Amer. Chem. Soc., 16 (1954), 3156; Borch R.F.,Tetrahedron Lett. 36, (1972), 3761; Martin, S.F., Synthesis, (1979),633; Ashwood M.S. et al., Synthesis, (1988), 379); Meyers, A.I., et al.,J. Amer. Chem. Soc., 104 (1982), 877-9; Matteson, D.S., et al., J. Org.Chem., 45 (1980) 1091-5)). Column chromatography was carried out usingthe technique described by Still, W.C. et al., J. Org. Chem., 43 (1978)2923 on Merck silica gel 60 (Art. 9385). HPLC was carried out using aWaters model 510 chromatograph interfaced via a system module to aWaters 490 multiwavelength detector to a reversed phase C₁₈ column (250× 4 mm, 5 μm, 100 Å. Retention times are given in minutes.

EXAMPLE 1 Method A(R)-1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-3-piperidine carboxylic acidethyl ester

The (R)-enantiomer of ethyl nipecotate (100 g, 0.64 mole) (Akkerman,A.M. et al., Gazz.Chim.Ital., 102 (1972) 189) was mixed in dry acetone(300 ml) with 2-bromoethanol (85 g, 0.68 mole), dried, powderedpotassium carbonate (188 g, 1.28 mole) and potassium iodide (21.6 g,0.13 mole). The reaction mixture was stirred at room temperature for 18h and at reflux for 24 h. Filtration of the reaction mixture andevaporation of the resultant filtrate gave(R)-1-(2-hydroxyethyl)nipecotic acid ethyl ester as an oil, which waspurified by distillation in vacuo (110°-° C., 0.1 mmHg), yield (72.2 g,56%). TLC: rf 0.20 (SiO₂ ; dichloromethane/methanol 19/1).

A sample of the above alcohol (140 g, 0.70 mole) was dissolved intoluene (400 ml) and thionyl bromide (80 ml, 0.77 mole) was introducedwith vigorous stirring. After 1.5 h the exotherm reaction had subsidedand diethyl ether (400 ml) was added. The resultant precipitate wascollected by filtration and washed with diethyl ether. The solid wastriturated with ethyl acetate, again collected on a filter and dried toprovide (R)-1-(2-bromoethyl)nipecotic acid ethyl ester hydrobromide (175g, 73%) as a white solid, m.p. 210°-215° C.

Diphenylacetaldehyde (4.9 g, 0.025 mole) was added dropwise to a mixtureof sodium hydride (1.5 g, 0.05 mole, 80% oil dispersion) and dry toluene(25 ml) at 0° C. This mixture was stirred at room temperature for 0.5 h,heated to 50° C. and allowed to cool to room temperature. The above(R)-1-(2-bromoethyl)nipecotic acid ethyl ester hydrobromide (8.6 g,0.025 mole) was added portionwise whilst the temperature was kept below30° C. with an ice-water bath. After being stirred for 1 h the reactionmixture was filtered, and the filtrate was evaporated to dryness. Flashchromatography of the residue on silica gel (200 g) using a mixture ofheptane and tetrahydrofuran (4/1) as eluent provided the title compound(6.6 g, 69%) as an oil. Tlc: rf 0.24 (SiO₂ ; heptane/THF 7/3).

EXAMPLE 2 (R)-1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-3-piperidinecarboxylic acid hydrochloride

(R)-1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-3-piperidine carboxylic acidethyl ester (example 1) (3.0 g, 0.079 mol) was dissolved in ethanol (20ml) and 12 N sodium hydroxide solution (2.0 ml) was introduced. Afterstirring the solution at room temperature for 2.5 h, 37% hydrochloricacid (ca. 2.2 ml) was added, with acidity measured at pH 2.Dichloromethane (300 ml) was introduced, and the mixture was dried(MgSO₄). Filtration and evaporation of the filtrate gave a solid, whichwas triturated with diethyl ether, to give the title compound (2.65 g,86%) as a white solid, m.p. 210°-216° C.

C₂₂ H₂₅ ClNO₃.HCl requires: C, 68.1; H, 6.8; N, 3.6; Cl, 9 15. Found: C,67.6; H, 6.7; N, 3.65; Cl, 9.0%.

EXAMPLE 3Z-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidinecarboxylic acid hydrochloride

Z-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidinecarboxylic acid ethyl ester (2.0 g, 0.0051 mol) (prepared as describedin Method A) was dissolved in ethanol (8 ml) and 12N sodium hydroxidesolution (1.3 ml) was introduced. After stirring the solution at roomtemperature for 2 h, 37% hydrochloric acid (ca. 1.8 ml) was added withcooling, followed by dichloromethane (300 ml) and the mixture was dried(Na₂ SO₄). Filtration and evaporation of the filtrate gave a residue,which was co-evaporated with acetone. The solid product was trituratedwith ethyl acetate, collected by filtratiion and dried in vacuo to givethe title compound (0.70 g, 34%), m.p. 206°-211° C.

C₂₃ H₂₇ NO₃.HCl requires C, 68.7; H, 7.0; N, 3.5; Cl, 8.8. Found: C,67.7; H, 7.1; N, 3.5; Cl, 8.9%

EXAMPLE 4E-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidinecarboxylic acid hydrochloride

E-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidinecarboxylic acid ethyl ester (1.1 g, 0.0028 mol) (prepared as describedin Method A) was dissolved in ethanol (5 ml) and 12N sodium hydroxidesolution (0.7 ml) was introduced. After stirring the solution at roomtemperature for 2h, 37% hydrochloric acid solution (ca. 1.0 ml) wasadded (with cooling) followed by dichloromethane (300 ml) and themixture was dried (Na₂ SO₄). Filtration and evaporation of the filtrategave a residue, which was co-evaporated with acetone. The solid productwas triturated with ethyl acetate, collected by filtration and dried invacuo to provide the title compound (0.70 g, 62%), m.p. 195-196.

C₂₃ H₂₇ NO₃.HCl requires C, 68.7; H, 7.0; N, 3.5; Cl, 8.8 Found: C,68.1; H, 7.2; N, 3.4; Cl, 8.7%.

EXAMPLE 5 E orZ-(R)-1-[2-[[2-(2-Chlorophenyl)-2-phenylethenyl]oxy]-ethyl]-3-piperidinecarboxylic acid hydrochloride

E orZ-(R)-1-[2-[[2-(2-Chlorophenyl)-2-phenylethenyl]oxy]-ethyl]-3-piperidinecarboxylic acid ethyl ester (1.0 g, 0.0024 mol) (prepared as describedin Method A) was dissolved in ethanol (10 ml) and 10N sodium hydroxidesolution (2.42 ml) was introduced. After stirring the solution at roomtemperature for 5 h, water (100 ml) was added and the mixture wasneutralized with 2N hydrochloric acid solution. Evaporation of ethanolunder reduced pressure gave an aqueous solution, which was acidified topH 0.5 with 2N hydrochloric acid solution and extracted withdichloromethane (4 × 100 ml). The combined extracts were dried (Na₂ SO₄)and evaporated to an oil, which was dissolved in a trace of methanol.Toluene (20 ml) was introduced, and the product solution was heated on asteam bath. On cooling the title compound (0.64 g, 62%), a whitecrystalline solid, was collected and dried in vacuo. M.p. softens at170°, melts at 198°.

C₂₂ H₂₃ ClNO₃.HCl requires C, 62.6; H, 5.7; N, 3.2; Cl, 16.8 Found: C,62.5; H, 6.0; N, 3.2; Cl, 16.6%.

EXAMPLE 6 E orZ-(R)-1-[2-[[2-(2-Chlorophenyl)-2-phenylethenyl]oxy]-ethyl]-3-piperidinecarboxylic acid hydrochloride

E orZ-(R)-1-[2-[[2-(2-Chlorophenyl)-2-phenylethenyl]oxy]-ethyl]-3-piperidinecarboxylic acid ethyl ester (1.0 g, 0.0024 mol) (opposite geometricisomer of example 6) was dissolved in ethanol (20 ml) and 10N sodiumhydroxide solution (2.42 ml) was introduced. After stirring the reactionmixture at room temperature for 16 h, water (100 ml) was added and themixture was neutralized with 2N hydrochloric acid solution Evaporationof ethanol under reduced pressure gave an aqueous solution, which wasacidified to pH 1 with 2N hydrochloric acid and extracted withdichloromethane (4 × 100 ml). The combined extracts were dried (Na₂ SO₄)and evaporated to a solid, which was recrystallized frommethanol/toluene to give the title compound (0.58 g, 56%) as whitecrystals (after drying in vacuo), m.p. 227°-8°.

C₂₂ H₂₃ ClNO₃.HCl requires C, 62.6; H, 5.7; N, 3.3; Cl, 16.8 Found: C,62.6; H, 6.1; N, 3.2; Cl, 16.7%.

EXAMPLE 7 (R)-1-[3-[[2,2-Diphenylethenyl]oxy]propyl]-3-piperidinecarboxylic acid hydrochloride

(R)-1-[3-[[2,2-Diphenylethenyl]oxy]propyl]-3-piperidine carboxylic acidethyl ester (0.60 g, 0.0015 mol) (prepared as described in Method A) wasdissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.4 ml)was introduced. After stirring the solution at room temperature for 2 h,37% hydrochloric acid (ca. 0.52 ml) was added with cooling followed bydichloromethane (250 ml). The mixture was dried (Na₂ SO₄). Filtrationand evaporation of the filtrate gave a residue, which was co-evaporatedwith acetone. The solid product was triturated with acetone, collectedby filtration and dried in vacuo to give the title compound (0.30 g,50%), m.p. 176°-180°.

C₂₃ H₂₇ NO₃.HCl.0.25H₂ O requires C, 68.0; H, 7.1; N, 3.45; Cl, 8.7Found: C, 67.9; H, 7.1; N, 3.4; Cl, 8.3%

EXAMPLE 8 (R)-1-[2-[[2-(2-Methylphenyl)-2-(3-methyl-2-thienyl)etheyl]oxy]ethyl]-3-piperidine carboxylic acid hydrochloride

(R)-1-[2-[[2-(2-Methylphenyl)-2-(3-methyl-2-thienyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (6.0 g,0.0133 mol) (prepared as described in Method A) was dissolved in ethanol(100 ml) and 10N sodium hydroxide solution (13.3 ml) was introduced.After stirring the solution at room temperature for 3 h water (200 ml)was added, and the ethanol was evaporated under reduced pressure. Theaqueous solution was acidified to pH 1 with 2N hydrochloric acidsolution and extracted with dichloromethane (4 × 150 ml). The combinedextracts were dried (MgSO₄) and evaporated to a solid, which wasrecrystallized from methanol/toluene/cyclohexane to give the titlecompound (4.09 g, 68%) as white crystals, m.p. 207°-12° (after drying invacuo).

C₂₂ H₂₇ NO₃ S.HCl.0.33PhCH₃ requires C, 64.6; H, 6.8; N, 3.1; Cl, 7.8;S, 7.6 Found: C, 64.6; H, 6.8; N, 3.1; Cl, 7.8; S, 7.3%.

EXAMPLE 9 E or Z-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid hydrochloride

E or Z-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)-ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.40 g, 0.00097mol) (prepared as described in Method A) was dissolved in ethanol (5 ml)and 12 N sodium hydroxide solution (0.3 ml) was introduced. Afterstirring the solution at room temperature for 5 h, 37% hydrochloric acidsolution was added until the pH was measured as ca. 1. Dichloromethane(250 ml) was introduced, and the resultant precipitate was dissolved byaddition of ice portionwise with vigorous stirring. The organic phasewas separated, dried (Na ) and evaporated to a residue, which wasco-evaporated with acetone. Recrystallization from acetone provided thetitle compound (0.10 g, 24%) as a white solid, m.p. 193°-195°.

C₂₃ H₂₆ FNO₃.HCl requires C, 65.8; H, 6.5; N, 3.3; Cl, 8.4. Found: C,65.4; H, 6.6; N, 3.7; Cl, 8.2%.

EXAMPLE 10 Z or E-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid hydrochloride

Z orE-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid ethyl ester (0.50 g, 0.22123 mol) (prepared as describedin Method A) (opposite geometric isomer of example 9) was dissolved inethanol (5 ml) and 12 N sodium hydroxide solution (0.3 ml) wasintroduced. After stirring the solution at room temperature for 5 h, 37%hydrochloric acid solution was added until the pH was measured as ca. 1.Dichloromethane (250 ml) was introduced, and the resultant precipitatewas dissolved by addition of ice with vigorous stirring. The organicphase was separated, dried (Na₂ SO₄) and evaporated to a residue, whichwas co-evaporated with acetone. Recrystallization from acetone providedthe title compound (0.10 g, 20%) as a white solid, m.p. 193°-195°

C₂₃ H₂₆ FNO₃.HCl requires C, 65.8; H, 6.5; N, 3.3, Cl, 8.4 Found: C,65.5; H, 6.6; N, 3.5; Cl, 8.3%.

EXAMPLE 11 Method B(R)-1-[2-[[2,2-bis(3-Methyl-2-thienyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid ethyl ester

2-(Triphenylmethoxy)ethanol (3.98 g, 0.013 mol) was dissolved in dry THF(50 ml) and a 2.5 M solution of butyllithium in hexane (5.5 ml, 0.0137mol) was added at 0° C. A solution of bromoacetic acid (1.81 g, 13.0mmol) was separately treated with a 2.5 M solution of butyllithium inhexane (5.5 ml, 13.7 mmol) at 0° C. before the two solutions were mixed.This reaction mixture was heated at reflux for 68 h, cooled, and water(200 ml) was added. Washing with ethyl acetate was followed byacidification of the aqueous phase with 0.5 M citric acid solution (50ml). Extraction with ethyl acetate (2 × 100 ml) and drying (MgSO₄)provided crude [2-(triphenylmethoxy)ethoxy]acetic acid (2.78 g, 58%).This acid was dissolved in dichloromethane (30 ml) anddicyclohexylcarbodiimide (1.72 g, 0.0083 mol) was added, followed by4-pyrrolidinopyridine (0.11 g, 0.00074 mol) and ethanol (0.89 ml, 2equiv.) (A. Hassner et al., Tetrahedron Lett. (1978) 4475). The reactionmixture was stirred for 16 h at room temperature and filtered to removedicyclohexyl urea. The filtrate was evaporated, and the residue waspurified by flash chromatography on silica gel (3 × 20 cm). Elution withcyclohexane containing 1-3% ethyl acetate provided the desired[2-(triphenylmethoxy)ethoxy]acetic acid ethyl ester (1.5 g, 50%) as anoil.

2-Bromo-3-methylthiophene (1.5 g, 0.0085 mol) and magnesium turnings(0.22 g) were heated gently in dry THF (30 ml) and the reaction rapidlybecame exothermic. After 0.2 h the reaction mixture was heated at refluxfor 0.5 h, and the above ester (1.5 g, 0.0038 mol) was introduced as asolution in THF (20 ml). The mixture was again heated at reflux for 0.5h, cooled, and ammonium chloride solution (100 ml) was added. Stirringfor 0.5 h at room temperature was followed by extraction with ethylacetate (3 × 70 ml). The combined extracts were dried (MgSO₄) andevaporated. The residue was dissolved in a mixture of 2 N hydrochloricacid (50 ml), THF (50 ml) and ethanol (50 ml) and the solution washeated at 50° C. for 1 h, and basified to pH 9 5 with sodium hydroxidesolution The organic solvents were removed in vacuo and the aqueousresidue was extracted with ethyl acetate (3 × 75 ml). Drying of thecombined extracts (MgSO₄) and evaporation gave an oil, which waspurified by flash chromatography on silica gel (2 × 15 cm). Elution withcyclohexane/ethylacetate (9/1) provided2-[2-(2-Hydroxyethoxy)-1-(3-methyl-2-thienyl)ethenyl]-3-methylthiophene(0.54 g, 50%) as a gum.

The above alcohol (0.53 g, 0.0019 mol) was dissolved in dry toluene (20ml) and the solution was cooled to 0° C. A solution of n-butyllithium(2.5 M in hexane) (0.9 ml, 0.0023 mol) was introduced, and the reactionmixture was allowed to stand at 0° C. for 1 h after which time asolution of p-toluenesulphonyl chloride (0.47 g, 0.0025 mol) in toluene(10 ml) was added. The mixture was left at room temperature for 20 h andto the resulting tosylate solution was added the (R)-enantiomer of ethylnipecotate (0.59 g, 0.0038 mol) and powdered, dried potassium carbonate(1.04 g, 0.0075 mol). The temperature was increased to 80° C. andmaintained for 50 h. The reaction mixture was cooled and water (50 ml)was added. The toluene phase was separated and the water phase wasextracted with ethyl acetate (50 ml). The combined organic extracts weredried (MgSO₄) and evaporated to give an oil, which was purified by flashchromatography on silica gel. Elution with cyclohexane/ethyl acetate(19/1-5/1) provided the title compound (0.25 g, 31%) as a gum. TLC: rf0.26 (Si02; heptane/THF 7/3).

EXAMPLE 12(R)-1-[2-[[2,2-bis(3-Methyl-2-thienyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid

(R)-1-[2-[[2,2-bis(3-Methyl-2-thienyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic ethyl ester (420 mg, 1 mmol) (example 11) was dissolved inethanol (20 ml) and 10 N sodium hydroxide solution (1.00 ml) wasintroduced. After 3 h at room temperature the pH of the solution wasadjusted to 9 with 2 N hydrochloric acid. The ethanol was removed byevaporation and the pH of the solution was adjusted to 2.5. Extractionwith dichloromethane (4 × 15 ml), drying of the combined extracts(MgSO₄) (charcoal decolourisation) and evaporation of the filtrateprovided a residue, which was recrystallized from water. This providedthe title compound (0.34 g, 84%) as a cream solid, m.p. 55°-70° C. TLC:rf 0.37 (SiO₂, CH₂ Cl₂ /MeOH 1/1).

C₂₀ H₂₅ NO₃ S₂.3/4 H₂ O requires C, 59.3; H, 6.6; N, 3.45; S, 15.8; Cl,2.9. Found: C, 59.3; H, 6.6; N, 3.5; S, 15.85%.

EXAMPLE 131-[2-[[2,2-bis(2-Methylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride

1-[2-[[2,2-bis(2-Methylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester (0.70 g, 0.0018 mol) (prepared as described in MethodB) was dissolved in ethanol (30 ml) and 10 N sodium hydroxide solution(1.79 ml) was introduced. The reaction mixture was stirred at roomtemperature for 2.5 h and water (100 ml) was added, followed by 2 Nhydrochloric acid solution to pH 10. Ethanol was removed by evaporationunder reduced pressure, and the aqueous solution was washed with ethylacetate (20 ml). The aqueous phase was separated, acidified to pH 2 with2 N hydrochloric acid solution, and extracted with dichloromethane (4 ×50 ml). The combined extracts were dried (MgSO₄) and the residue wascrystallized from propanol/toluene to give the title compound (0.53 g,76%), m.p. 195°-198°.

C₂₄ H₂₇ NO₃.HCl requires C, 69.65; H, 6.8; N, 3.4; Cl, 8.55 Found: C,69.6; H, 6.85; N, 3.2; Cl, 8.1%.

EXAMPLE 14 Method C a.1-[2-(2-Bromoethoxy)-1-(2-methylphenyl)ethenyl]-4-fluoro-2-methylbenzene

(4-Fluoro-2-methylphenyl)-(2-methylphenyl)acetaldehyde (3.5 g, 0.0144mol) was dissolved in dry THF (20 ml) and added dropwise to a suspensionof sodium hydride (60% oil dispersion) (0.63 g, 0.0158 mol) in drytetrahydrofuran (30 ml). The mixture was stirred at room temperature for1 h and heated at reflux for 0.5 h. After cooling 1,2-dibromoethane(12.4 ml, 10 equiv.) was added, and the reaction mixture was allowed tostand at room temperature for 192 h. The reaction mixture was filteredand evaporated. The residue was pumped in vacuo, but still contained ca.30% starting aldehyde, so the above procedure was repeated.

The filtered reaction mixture was evaporated and to the residue water(100 ml), saturated brine (100 ml) and ethyl acetate (200 ml) wereadded. The aqueous phase was separated and washed with ethyl acetate(100 ml). The combined ethyl acetate extracts were washed with brine(100 ml), dried (MgSO₄) and evaporated. The crude title compound (2.3 g,ca. 46%) was used in the next stage, without further purification.

b (R)-1-[2-[[2-(4-Fluoro-2-methylphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester

1-[2-(2-Bromethoxy)-1-(2-methylphenyl)ethenyl]-4-fluoro-2-methylbenzene(1.15 g, 0.0033 mol), the (R)-enantiomer of ethyl nipecotatehydrochloride (see example 1) (1.92 g, 0.0099 mol) and dried potassiumcarbonate (2.28 g, 0.0165 mol) were stirred in acetone (100 ml) atreflux temperature for 54 h.

The cooled reaction mixture was filtered, and the filtrate wasevaporated. The residue was purified by flash chromatography on silicagel (4,5 × 15 cm) eluting with heptane/ethyl acetate (9:1→4:1) to givethe title compound as a gum (0.57 g, 40%), TLC rf 0.4 (SiO₂, ethylacetate/heptane 1/1).

c. (R)-1-[2-[[2-(4-Fluoro-2-methylphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid hydrochloride

(R)-1-[2-[[2-(4-Fluoro-2-methylphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.56 g,0.0013 mol) was dissolved in ethanol (6 ml) and 10 N sodium hydroxidewas introduced. After stirring the solution at room temperature for 2 h,water (200 ml) was added, and the ethanol was evaporated under reducedpressure. The aqueous solution was acidified to pH 5 with 2Nhydrochloric acid solution and extracted with dichloromethane (3 × 100ml).

The combined extracts were dried (MgSO₄) and evaporated to a residuewhich was treated with toluene (20 ml) and the mixture was filtered. Tothe filtrate, methanol (0.06 ml) and chlorotrimethylsilane (0.20 ml)were added, and the hydrochloride salt precipitated. Evaporation of themixture, followed by crystallization of the residue from tracemethanol/toluene provided the title compound (0.38 g, 67%), m.p. softensat 195o, melts finally at 210°.

C₂₄ H₂₈ FN O₃.HCl requires C, 66.4; H, 6.7; N, 3.2; Cl, 8.2 Found: C,66.3; H, 6.8; N, 3.1; Cl 8.4%.

EXAMPLE 15 1-[2-[[2-(4-Fluoro-2-methylphenyl)-2-(2-methyl-phenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acidhydrochloride

1-[2-[[2-(4-Fluoro-2-methylphenyl)-2-(2-methyl-phenyl)ethenyl]oxy]ethyl]-1,2,5,6=tetrahydro-3-pyridine carboxylic acid methylester (0.74 g, 0.0018 mol) (prepared as described in Method C) wasdissolved in ethanol (15 ml) and 10 N sodium hydroxide solution (1.8 ml)was introduced. After stirring the reaction mixture for 2 h at roomtemperature TLC indicated that saponification was incomplete, so further10 N sodium hydroxide solution (1.8 ml) was added, and the reactionmixture was heated for 10 min. at 40° C. Water (400 ml) was added, andthe solution was extracted with diethyl ether (100 ml). The aqueouslayer was acidified to pH 5 with 2N hydrochloric acid solution andextracted with dichloromethane (4 × 50 ml). The combined extracts weredried (MgSO₄) and evaporated to a residue (0.61 g) which was dissolvedin toluene (50 ml). Methanol (0.2 ml) and chlorotrimethylsilane (0.216ml) were added, and after mixing, a layer of cyclohexane (ca. 30 ml) wasadded. After storing this mixture at 4° for 18 h, the title compound wascollected by filtration (0.60 g, 77%), m.p. 190°-201° (after drying invacuo).

C₂₄ H₂₆ FNO₃.HCl.0.1PhCH₃ requires C, 67.3; H, 6.4; N, 3.2; Cl, 8.0Found: C, 67.1; H, 6.4; N, 3.1; Cl, 8.1%

EXAMPLE 16 Method D a.1-[2-(2-Bromoethoxy)-1-(3-fluorophenyl)ethenyl]-3-fluorobenzene

bis(3-Fluorophenyl)acetaldehyde (4.82 g, 0.0208 mol) was dissolved indichloromethane (50 ml) and tetra-n-butyl ammonium bromide (0.67 g,0.00208 mol) was added. 12 N sodium hydroxide solution (50 ml) and1,2-dibromoethane (17.9 ml, 0.208 mol) were introduced and the mixturewas stirred vigorously at room temperature for 20 h. Dichloromethane(100 ml) and saturated brine (50 ml) were added, and the phases wereseparated. The aqueous phase was extracted further with dichloromethane(50 ml) and the combined dichloromethane extracts were washed with water(2 × 75 ml) and saturated brine (50 ml). Drying of the dichloromethanesolution (Na₂ SO₄) and evaporation provided the title compound as an oil(6.66 g, 95%), TLC rf 0.71 (SiO₂ dichloromethane).

b.1-[2-[[2,2-bis(3-Fluorophenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylicacid methyl ester hydrochloride

To 1-[2-(2-Bromoethoxy)-1-(3-fluorophenyl)ethenyl]-3-fluorobenzene (6.57g, 0.0194 mol) in acetone (100 ml) was added1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester hydrochloride(guvacine methyl ester hydrochloride) (5.57 g, 0.0291 mol), driedpotassium carbonate (8.03 g, 0.0581 mol) and potassium iodide (0.32 g,0.0019 mol). The suspension was stirred at room temperature for 50 h andfiltered. The filtrate was evaporated to an oil (8.2 g) which wasdissolved in ethyl acetate (100 ml). Water (40 ml) was added, and the pHof the aqueous phase was adjusted to 4 with 34% aqueous tartaric acid.The aqueous layer was separated, and the organic phase was washed withpH 4 aqueous tartaric acid (20 ml), after which water (40 ml) was added.The pH of the aqueous phase was adjusted to ca. 8 with 2 N sodiumhydroxide solution, and the phases were separated. The organic phase waswashed with saturated brine (10 ml), dried (Na₂ SO₄) and evaporated toan oil.

To this oil in toluene (20 ml) at 45° was added methanol (0.68 ml,0.0167 mol) followed by chlorotrimethylsilane (1.173 g, 0.0156 mol).After stirring at room temperature for 18 h the ester hydrochloride hadprecipitated, and the suspension was cooled to 0° C. for 2 h. The solidwas collected by filtration, washed with cold toluene (15 ml) andsuspended in dry diethyl ether (25 ml). Filtration provided the titlecompound (3.56 g, 59%) as a white solid, TLC rf 0.68 (SiO₂:dichloromethane/methanol/acetic acid 20:2:1).

c.1-[2-[[2,2-bis(3-Fluorophenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride

To1-[2-[[2,2-bis(3-Fluorophenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (3.50 g, 0.0078 mol) in 96%aqueous ethanol (25 ml) at 5° was added 12 N sodium hydroxide solution(2.I ml). After stirring the solution at room temperature for 4.5 h thepH was adjusted to 6 with 4 N hydrochloric acid solution, and themixture was evaporated to an oil. Ethyl acetate (50 ml) and water (20ml) were added, and the organic phase was separated. The aqueous phasewas washed with ethyl acetate (25 ml) and the combined organic phaseswere washed with saturated brine (10 ml). The ethyl acetate phase wasdried (Na₂ SO₄) and the residue was co-evaporated with dichloromethane(3 × 15 ml).

To the residue in toluene (22 ml) at 45° was added methanol (0.225 ml)and chlorotrimethylsilane (0.705 ml). On cooling and stirring at roomtemperature for 18 h the product hydrochloride had precipitated, and thesuspension was cooled to 0° for 1.5 h. The solid was collected byfiltration and dried in vacuo to give the desired product (2.65 g, 80%).Recrystallization from water provided the title compound (1.60 g, 53%),m.p. 158°-9°.

C₂₂ H₂₁.F₂ NO₃.HCl.0.3H₂ O requires C, 61.8; H, 5.1; N, 3.3; Cl, 8.3Found: C, 61.5; H, 5.3; N, 3.1; Cl, 8.4%.

EXAMPLE 17(R)-1-[2-[[2,2-bis(2-Methylphenyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid hydrochloride

(R)-1-[2-[[2,2-bis(2-Methylphenyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid ethyl ester (2.20 g, 0.0054 mol) (prepared as describedin Method D) was dissolved in ethanol (20 ml) and 10 N sodium hydroxidesolution (7 ml) was introduced. After stirring the solution at roomtemperature for 3 h, water (300 ml) was added, and the solution waswashed with diethyl ether (100 ml). The aqueous layer was washed furtherwith diethyl ether (100 ml). The pH of the aqueous layer was adjusted to5 and then extracted with dichloromethane (4 × 100 ml). The combinedextracts were dried (MgSO₄), evaporated, and the residue was dissolvedin toluene (50 ml). Methanol (0.4 ml) and chlorotrimethylsilane (0.7 ml)were added, and the product precipitated This solid was collected byfiltration and recrystallized from water to give the title compound (1.4g, 62%), m.p. 217°-226° (after drying in vacuo).

C₂₄ H₂₉ N O₃.HCl requires C, 69.3; H, 7.3; N, 3.4; Cl, 8.5 Found: C,69.4; H, 7.4; N, 3.3; Cl, 8.5%.

EXAMPLE 18(R)-1-[2-[[2,2-bis(4-Fluoro-2-methylphenyl)ethenyl]oxy]-ethyl]-3-piperidinecarboxylic acid hydrochloride

(R)-1-[2-[[2,2-bis(4-Fluoro-2-methylphenyl)ethenyl]oxy]-ethyl]-3-piperidinecarboxylic acid ethyl ester (1.72 g, 0.0039 mol) (prepared as describedin Method D) was dissolved in ethanol (20 ml) and 10 N sodium hydroxidesolution (4 ml) was introduced. The solution was stirred at roomtemperature for 3 h and water (100 ml) was added. The solution wasextracted with diethyl ether (2 × 100 ml) and the aqueous phase wasacidified to pH 5 with 2 N hydrochloric acid solution. Extraction withdichloromethane (4 × 80 ml) and drying of the combined extracts (MgSO₄)followed by evaporation gave a residue, which was dissolved in toluene(50 ml). Methanol (0.16 ml) and chlorotrimethylsilane (0.51 ml) wereadded, and the product precipitated. The mixture was evaporated to asolid and recrystallized from toluene to give the title compound as awhite crystalline solid (0.78 g, 44%), m.p. 175°-185° (decomp.)

C₂₄ H₂₇ FNO₃.HCl requires C, 63.8; H, 6.2; N, 3.1; Cl, 7.8 Found: C,64.1; H, 6.3; N, 3.0; Cl, 7.3%

EXAMPLE 19 E or Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid hydrochloride

E or Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.50 g,0.0012 mol) (prepared as described in Method D) was dissolved in ethanol(15 ml) and 12 N sodium hydroxide solution (0.2 ml) was introduced.After stirring the solution at room temperature for 6 h, ice (100 g) wasadded, and the pH of the reaction mixture was adjusted to ca. 7 with 37%hydrochloric acid solution Dichloromethane (200 ml) was added, and thepH was further adjusted to <2 with 37% hydrochloric acid solution. Thedichloromethane phase was dried (Na₂ SO₄) and evaporated to a solid (0.3g, 60%), m.p. 188°-192°

C₂₄ H₂₉ NO₄.HCl.0.25H₂ O requires C, 66.0; H, 7.0; N, 3.2; Cl, 8.2Found: C, 66.1; H, 7.2; N, 3.1; Cl, 8.1%.

EXAMPLE 20 E or Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid hydrochloride

E or Z-(R)-1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.80 g,0.0019 mol) (opposite geometric isomer of example 19) was dissolved inethanol (15 ml) and 12 N sodium hydroxide solution (0.3 ml) wasintroduced. After stirring the solution at room temperature for 6 h, ice(50 g) was added, and the pH of the reaction mixture was adjusted to ca.7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) wasadded, and the pH was further adjusted to <2 with 37% hydrochloric acidsolution. The dichloromethane phase was dried (Na₂ SO₄) and evaporatedto a solid (0.35 g, 44%), m.p. 198°-202°.

C₂₄ H₂₉ NO₄.HCl requires C, 66.7; H, 7.0; N, 3.2; Cl, 8.2 Found: C,66.5; H, 7.2; N, 3.0; Cl, 7.6.

EXAMPLE 211-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride

1-[2-[[2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester (1.15 g, 0.0027mol) (prepared as described in Method D) was dissolved in ethanol (15ml) and 12 N sodium hydroxide solution (0.5 ml) was introduced. Afterstirring the solution at room temperature for 4 h, ice (30 g) was added,and the pH of the reaction mixture was adjusted to ca. 7 with 37%hydrochloric acid solution. Dichloromethane (200 ml) was added, and thepH was further adjusted to ca. 1 with 37% hydrochloric acid solution.Water was added until the solid material was dissolved, and thedichloromethane phase was dried (Na₂ SO₄) and evaporated to an oil,which was co-evaporated three times with acetone. The residue wastriturated with diethyl ether to give the title compound (0.60 g, 52%),which gave HPLC retention times of 17.1 and 17.6 min. for the geometricisomers (gradient elution, water/20-80% acetonitrile, both containing0.1% TFA).

C₂₄ H₂₈ NO₄.0.8HCl.0.8H₂ O requires C, 65.8; H, 7.0; N, 3.2; Cl, 6.3Found: C, 65.3; H, 7.0; N, 3.2; Cl, 6.9%.

EXAMPLE 221-[2-[[2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride

1-[2-[[2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic methyl ester (0.60 g, 0.0014 mol)(prepared as described in Method D) was dissolved in ethanol (5 ml) and12 N sodium hydroxide solution (0.35 ml) was introduced. After stirringthe solution at room temperature for 3 h, 37% hydrochloric acid solutionwas added, until the pH was measured as ca. 1. Dichloromethane (200 ml)was introduced, and the mixture was dried (Na₂ SO₄), filtered andevaporated to a residue, which was co-evaporated twice with acetone. Theresidue was recrystallized from acetone/ethyl acetate to give the titlecompound (0.33 g, 55%) as white crystals, m.p. 168°-170° HPLC retentiontimes 16.12 and 18.42 for the geometric isomers (gradient elution,water/20-80% acetonitrile, both phases containing 0.1% TFA).

E orZ-1-[2-[[2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride

E orZ-1-[2-[[2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester (0.55 g, 0.0013mol) (prepared as described in Method D) was dissolved in ethanol (5 ml)and 12 N sodium hydroxide solution (0.33 ml) was introduced. Afterstirring the solution at room temperature for 3 h, 37% hydrochloric acidsolution was added until the pH was measured as ca. 1. Dichloromethane(200 ml) was introduced, and the mixture was dried (Na₂ SO₄), filteredand evaporated to a residue, which was co-evaporated twice with acetone.Recrystallization from acetone/ethyl acetate provided the title compound(0.17 g, 30%) as a white solid, m.p. 214°-215°.

C₂₃ H₂ ClNO₃.HCl requires C, 63.6; H, 5.8; N, 3.2; Cl, 8.2 Found: C,63.2; H, 5.8; N, 3.4; Cl, 8.0%.

EXAMPLE 231-[2-[[2,2-bis(2-Ethylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride

1-[2-[[2,2-bis(2-Ethylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (1.40 g, 0.00323 mol) (prepared asdescribed in Method D) was dissolved in ethanol (10 ml) and 12 N sodiumhydroxide solution (0.8 ml) was introduced. After stirring the solutionat room temperature for 5 h, 37% hydrochloric acid solution was addeduntil the pH was measured as ca. 1. Dichloromethane (250 ml) wasintroduced, and the mixture was dried (Na₂ SO₄), filtered and evaporatedto a residue, which was co-evaporated with acetone. Recrystallizationfrom acetone provided the title compound (0.80 g, 57%) as a white solid,m.p. 162°-165°.

C₂₆ H₃₁ NO₃.HCl requires C, 70.7; H, 7.3; N, 3.2; Cl, 8.0 Found: C,70.5; H, 7.4; N, 3.6; Cl, 8.0%.

EXAMPLE 24(R)-1-[2-[[2,2-bis(2-Ethylphenyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid hydrochloride

(R)-1-[2-[[2,2-bis(2-Ethylphenyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid ethyl ester (1.20 g, 0.00275 mol) (prepared as describedin Method D) was dissolved in ethanol (10 ml) and 12 N sodium hydroxidesolution (0.7 ml) was introduced. After stirring the solution at roomtemperature for 5 h, 37% hydrochloric acid solution was added until thepH was measured as ca. 1. Dichloromethane (250 ml) was introduced, andthe mixture was dried (Na₂ SO₄), filtered and evaporated to a residue,which was co-evaporated with acetone. Recrystallization from acetoneprovided the title compound (0.85 g, 70%) as a white solid, m.p.205°-206°.

C₂₆ H₃₃ NO₃.HCl requires C, 70.3; H, 7.7; N, 3.2; Cl, 8.0 Found: C,70.0; H,7.8; N, 3.4; Cl, 7.9%.

EXAMPLE 251-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride

1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (4.33 g, 0.01147 mol) (prepared asdescribed in Method D) was dissolved in ethanol (50 ml) and 10 N sodiumhydroxide solution (11.5 ml) was introduced, followed by water (5 ml).The solution was stirred at room temperature for 2.5 h and stored at 4°C. for 18 h. 2 N hydrochloric acid solution was added until the pHreached ca. 2, and the mixture was extracted with dichloromethane (3 ×60 ml). The combined extracts were dried (MgSO₄) and evaporated to givea foam (4.24 g) which was crystallized from 2-propanol to provide thetitle compound (2.32 g, 52%) as a white solid, m.p. 173°-176°.

C₂₂ H₂₃ NO₃.HCl.0.2H₂ O requires C, 67.8; H, 6.3; N, 3.6; Cl, 9.1 Found:C, 67.7; H, 6.3; N, 3.4; Cl, 8.8%.

EXAMPLE 261-[2-[[2-(2-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride

1-[2-[[2-(2-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester hydrochloride(2.18 g, 0.0049 mol) (prepared as described in Method D) was dissolvedin ethanol (24 ml) and 12 N sodium hydroxide solution (1.83 ml) wasintroduced at 5°. The solution was stirred at room temperature for 2.5 hand stored at -10° for 18 h. The reaction mixture was evaporated to aresidue after the pH had been adjusted to 6.5 with 4 N hydrochloric acidsolution. Water (20 ml) and ethyl acetate (50 ml) were added, theaqueous layer was separated and extracted again with ethyl acetate (25ml). The combined ethyl acetate extracts were washed with saturatedbrine (40 ml), dried (M ) and evaporated to a residue, which wasco-evaporated with dichloromethane (3 × 40 ml). This residue (1.9 g) wasdissolved in toluene (15 ml) and methanol (0.2 ml) was introducedfollowed by chlorotrimethylsilane (0.62 ml). The mixture was stirred for18 h at room temperature and cooled to 0° for 2 h. The title compound(1.9 g, 91%) was obtained as white crystals, m.p. 183°-5°, after dryingin vacuo.

C₂₃ H₂₄ FNO₃.1.25HCl requires C, 64.7; H, 6.0; N, 3.3; Cl, 10.4 Found:C, 64.3; H, 6.0; N, 3.1; Cl, 9.9%

EXAMPLE 271-[2-[[2-(2,4-Dichlorophenyl)-2-(2-methylphenyl)ethenyl]-oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride

1-[2-[[2-(2,4-Dichlorophenyl)-2-(2-methylphenyl)ethenyl]-oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester hydrochloride(2.76 g, 0.0055 mol) (prepared as described in Method D) was dissolvedin ethanol (30 ml) and 12 N sodium hydroxide solution (2.1 ml) wasintroduced at 5°. The solution was stirred at room temperature for 3 hand stored at -10° for 18 h. The reaction mixture was evaporated to aresidue after the pH had been adjusted to 6.5 with 4 N hydrochloric acidsolution. Water (50 ml), ethyl acetate (50 ml) and dichloromethane (50ml) were added and the organic phase was separated. The aqueous phasewas further extracted with ethyl acetate (50 ml) dichloromethane (50 ml)and the combined organic extracts were dried (MgSO₄) and evaporated. Theresultant residue was co-evaporated twice with methanol and twice withcarbon tetrachloride to give a foam (2.7 g).

This foam was dissolved in toluene (20 ml) and methanol (0.23 ml) wasintroduced followed by chlorotrimethylsilane (0.71 ml) at 35°. Theproduct began to crystallize at around 40° and the mixture was stirredfor 18 h at room temperature and cooled to 0° C. for 2 h. The titlecompound (2.20 g, 84%) was obtained as white crystals, m.p. 187°-90°(decomp.) after drying in vacuo.

C₂₃ H₂₃ Cl₂ O₃.1.1HCl requires C, 58.5; H, 5.2; N, 3.0; Cl 8.3 Found: C,58.2; H, 5.1; N, 2.8; Cl, 8.1%.

EXAMPLE 281-[2-[[2,2-bis(2-Chlorophenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride

1-[2-[[2,2-bis(2-Chlorophenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester hydrochloride (3.60 g, 0.0075 mol)(prepared as described in Method D) was dissolved in ethanol (40 ml) and12 N sodium hydroxide solution (2.5 ml) was introduced at 5°. Thesolution was stirred at room temperature for 6 h and stored at -10° for18 h. The reaction mixture was evaporated to a residue after the pH hadbeen adjusted to 6.5 with 4 N hydrochloric acid solution. Water (10 ml)and ethyl acetate (50 ml) were added, and the ethyl acetate wasseparated. The ethyl acetate phase was washed with saturated brine (10ml) dried (Na₂ SO₄) and evaporated. The resultant residue was evaporatedto give a foam (3.1 g). This foam was dissolved in toluene (23 ml) andmethanol (0.30 ml) was introduced followed by chlorotrimethylsilane e(0.94 ml) at 35 °. The product began to crystallize at around 40° andthe mixture was stirred for 48 h at room temperature and cooled to 0° C.for 2 h. The title compound (2.5 g, 73%) was obtained as white crystals,m.p. 200°-203° (decomp.). TLC rf 0.16 (SiO₂,dichloromethane/methanol/acetic acid: 80/8/4).

EXAMPLE 291-[2-[[2,2-bis(4-Fluoro-2-methylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride

1-[2-[[2,2-bis(4-Fluoro-2-methylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid ethyl ester (1.27 g, 0.0029mol) (prepared as described in Method D) was dissolved in ethanol (30ml) and 10 N sodium hydroxide solution (10 ml) was introduced. Afterstirring the solution at room temperature for 1 h, water (500 ml) wasadded and the solution was washed with diethyl ether (2 × 100 ml). ThepH of the aqueous layer was adjusted to 5 using 2 N hydrochloric acidsolution and extracted with dichloromethane (3 × 200 ml). The combinedextracts were dried (MgSO₄), evaporated and the residue was dissolved intoluene (50 ml), and added to a solution of chlorotrimethylsilane (0.47ml) and methanol (0.15 ml) in toluene (100 ml). The precipitate wascollected by filtration after the mixture had been stored at roomtemperature for 18 h. This solid was recrystallized three times fromtoluene/trace methanol to give the title compound (0.85 g, 65%) as whitecrystals, m.p. 195°-20° (decomp.).

C₂₄ H₂₅ F₂ NO₃.HC1.0.2H₂ O requires C, 63.6; H, 5.9; N, 3.1; Cl, 7.9.Found: C, 63.6; H, 5.9; N, 3.1; Cl, 7.9%.

EXAMPLE 30(R)-1-[2-[[2-(2-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid hydrochloride

(R)-1-[2-[[2-(2-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidinecarboxylic acid ethyl ester (4.1 g, 0.0096 mol) (prepared as describedin Method D) was dissolved in ethanol (100 ml) and 18 N sodium hydroxidesolution (10 ml) was introduced. After stirring the solution at roomtemperature for 1 h water (500 ml) was added, and the solution waswashed with diethyl ether (2 × 100 ml). The pH of the aqueous phase wasadjusted to 1 using 2 N hydrochloric acid solution and extracted withdichloromethane (4 × 200 ml). The combined extracts were dried (M ),evaporated and the residue was crystallized from toluene/trace methanolto provide the title compound (3.47 g, 87%) as a white crystallinesolid, m.p. 231°-234°.

C₂₃ H₂₆ ClNO₃.HCl requires C, 63.3; H, 6.2; N, 3.2; Cl, 16.3. Found: C,63.2; H, 6.4; N, 3.1; Cl, 16.3%.

EXAMPLE 311-[2-[[(2-(2-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid hydrochloride

1-[2-[[(2-(2-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid ethyl ester (3.35 g, 0.0079mol) (prepared as described in Method D) was dissolved in ethanol (100ml) and 18 N sodium hydroxide solution (10 ml) was introduced. Afterstirring the solution at room temperature for 2 h, water (500 ml) wasadded, and the reaction mixture was washed with diethyl ether (2 × 100ml). The pH of the aqueous phase was adjusted to 1 using 2 Nhydrochloric acid solution and it was extracted with dichloromethane (4× 100 ml). The combined extracts were dried (MgSO₄), evaporated and thesolid residue was recrystallized from toluene/trace methanol to providethe title compound (2.2 g, 64%) as a white crystalline solid, m.p.196°-198°.

C₂₃ H₂ ClNO₃.HCl requires C, 63.6; H, 5.8; N, 3.2; Cl, 16.3. Found: C,63.6; H, 5.9; N, 3.1; Cl, 16.3%.

EXAMPLE 32(R)-1-[3-[[2,2-bis(4-Fluorophenyl)ethenyl]oxy]propyl]-3-piperidinecarboxylic acid hydrochloride

(R)-1-[3-[[2,2-bis(4-Fluorophenyl)ethenyl]oxy]propyl]-3-piperidinecarboxylic acid ethyl ester tartrate (3.8 g, 0.0065 mol) (prepared asdescribed in Method D) was dissolved in ethanol (25 ml) and 12 N sodiumhydroxide solution (2.2 ml) was introduced at 5° After stirring thesolution at room temperature for 4.8 h, the pH of the reaction mixturewas adjusted to ca. 7 with 4 N hydrochloric acid solution, and themixture was evaporated to a residue in vacuo. Water (25 ml) was added,and the mixture was extracted with dichloromethane (3 × 50 ml). Thecombined extacts were dried (MgSO₄) and evaporated to a foam, which wasdissolved in toluene (1.5 ml) and warmed to 40° Methanol (0.27 ml) wasintroduced followed by chlorotrimethylsilane (0.83 ml). The productprecipitated slowly, and after the suspension had been allowed to standfor 18 h at room temperature it was collected by filtration. The titlecompound (2.9 g, quant.) was obtained as white crystals, m.p. 177°-180°(after drying in vacuo). HPLC retention time 12.55 (gradient elution,water/35-50% acetonitrile, aqueous phase containing 0.1 M ammoniumsulphate solution).

EXAMPLE 33 Method E (R)-1-[2-[[2,2-Diphenylethyl]oxy]ethyl]-3-piperidinecarboxylic acid

(R)-1-[2-[[2,2-Diphenylethyl]oxy]ethyl]-3-piperidine carboxylic acidhydrochloride (120 mg, 0.31 mmol) was dissolved in methanol (5 ml) andstirred under an atmosphere of hydrogen for 2 h at room temperature inthe presence of 5% palladium on carbon catalyst (52% aqueous paste) andthen filtered. The filtrate was evaporated to dryness leaving a residue,which was dissolved in water. The aqueous solution was lyophilized togive the title compound (80 mg, 58% of the theoretical yield) as asolid, TLC rf 0.32 (SiO₂, methanol).

We claim:
 1. A compound which is (R)-1-3-piperidine carboxylic acid or apharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition suitable for use as an analgesic, anxiolytic,antidepressant, hypnotic and for treating epilepsy and muscular andmovement disorders, comprising (a) the compound according to claim 1 ora pharmaceutically acceptable salt thereof together with (b) apharmaceutically acceptable carrier or diluent.
 3. The pharmaceuticalcomposition according to claim 2 in the form of a dosage unit containingbetween 0.5 mg and 1000 mg of the compound (a).
 4. A method of treatingepilepsy, muscular and movement disorders, pain, anxiety, depression andsleeping disorders in a subject in need of such treatment comprisingadministering to said said subject an effective amount of the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereoftogether with a pharmaceutically acceptable carrier or diluent.
 5. Themethod of claim 4, wherein the compound (a) is administered in the formof a pharmaceutical composition together with a pharmaceuticallyacceptable carrier or diluent.